# Defining the pathological mechanisms of hereditary hearing loss

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $335,750

## Abstract

Project Summary
Numerous mutations associated with various forms of hereditary hearing loss (HHL) have been identified in
many genes. Defining the physiological roles of HHL genes and the pathological mechanisms of mutations
found in these genes is important for the development of remedies against HHL. This study will determine the
pathogenicity and pathological mechanisms of mutations found in two HHL genes, SLC26A4 and SLC26A5.
 SLC26A4 encodes an anion transporter, pendrin. Alterations of this gene are one of the common
causes of hereditary hearing loss, and over 300 missense mutations have been identified in this gene. In
order to define the pathological mechanisms of these mutations, it is important to know how these mutations
affect the function of pendrin and how the functional phenotypes correlate with disease phenotypes. To this
end, protein expression, membrane targeting, and anion transport functions of mutated pendrin proteins will
be characterized in a mammalian cell line. The results will be mapped onto a structural model so that
mechanistic insights for pendrin and other SLC26 proteins can be obtained. The large number of missense
mutations found in SLC26A4 makes these efforts systematic and thorough.
 SLC26A5 encodes a membrane-based motor protein, prestin, which is abundantly expressed in
OHCs. Its voltage-driven motor activity, electromotility, is demonstrated to be essential for normal cochlear
amplification. However, it remains unclear how electromotility is used in the amplification process.
Pathological characterizations of SLC26A5 mutations have been ambiguous due to the lack of this
fundamental knowledge. In this study, the importance of the rapid motor activity of prestin will be examined
using an animal model expressing prestin harboring an HHL-associated mutation that significantly slows the
motor kinetics of prestin. In addition, two novel SLC26A5 missense mutations recently found in a patient with
congenital hearing loss will be characterized in order to further gain insights as to how prestin contributes to
the cochlear amplification process and OHC maintenance.
 Functional characterization of disease-associated mutations is not only important for assessing their
pathogenicity, but also beneficial for appreciating the normal physiological roles of genes and defining the
molecular mechanisms of the gene products. Successful completion of this study allows unequivocal
pathological characterization of mutations found in SLC26A4 and SLC26A5.!

## Key facts

- **NIH application ID:** 10058834
- **Project number:** 5R01DC017482-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Kazuaki Homma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,750
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058834

## Citation

> US National Institutes of Health, RePORTER application 10058834, Defining the pathological mechanisms of hereditary hearing loss (5R01DC017482-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10058834. Licensed CC0.

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